The overall goal of this project is to assess genetic and immunological factors that contribute to the pathogenesis of neurological disease. Particular attention is focused on multiple sclerosis (MS) since this disease is thought to have an immunopathological basis. Genetic and immunological factors are being examined in well characterized, sporatic patients and in affected or unaffected members of families with multiple affected members and in identical or nonidentical twins either concordant or discordant for MS. Several new multiplex families have been identified and used to examine the cellular immune response to myelin basic protein (MBP). A T-cell response to MBP is present in both affected and unaffected individuals and does not appear to differ in HLA restrction, peptide specificity or T-cell receptor usage between affected and unaffected individuals. Various forms of immunosuppressive therapy are being tested in the treatment of MS using MRI parameters as a means of measuring efficacy and a subset of patients show a significant improvement with treatment with immunosuppressive drugs such as cyclophosphamide or cyclosporine supporting the hypothesis that MS has an immunological basis. Patients with other inflammatory diseases of the central nervous system are bing examined to assess disease mechanisms. HTLV-I associated myelopathy-tropical spastic paraplegia (HAM-TSP) is being evaluated since it may represent an example of viral-induced immunopathological disease. Serpositive patients either with or without clinical disease have been identified. Immunological studies indicate that disease correlates with the presence of HTLV-I cytotoxic T cells (CTL). New techniques for identification of the virus genome in blood and tissue are being developed. HTLV-II has been identified in one patient with a neurological disease identical to HAM-TSP indicating that retroviruses other than HTLV-I can cause neurological disease.